Tsang-Bin Tzeng - Academia.edu (original) (raw)

Papers by Tsang-Bin Tzeng

Research paper thumbnail of Pharmacokinetic/Pharmacodynamic Relationship of the Duration of Vasodilating Action of Organic Mononitrates in Rats1

J Pharmacol and Exp Ther, 1992

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the du... more Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (Tn). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the dassical Hill equation, with similar slope but different EC

Research paper thumbnail of Pharmacokinetic/Pharmacodynamic Relationship of the Duration of Vasodilating Action of Organic Mononitrates in Rats1

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the du... more Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (Tn). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the dassical Hill equation, with similar slope but different EC

Research paper thumbnail of Pharmacokinetic/Pharmacodynamic Relationship of the Duration of Vasodilating Action of Organic Mononitrates in Rats1

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the du... more Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (Tn). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the dassical Hill equation, with similar slope but different EC

Research paper thumbnail of Absorption Kinetics of Diclofenac in Dental Patients After Molar Extraction

Clinical Pharmacology & Therapeutics, Feb 1, 1996

ABSTRACT

Research paper thumbnail of Population pharmacokinetics of rosuvastatin in normal subjects and subjects with dyslipidemia

Clinical Pharmacology & Therapeutics, Feb 1, 2004

Purpose Data from two clinical studies (hyperCholesterolaemia in cHildren and Adolescents taking ... more Purpose Data from two clinical studies (hyperCholesterolaemia in cHildren and Adolescents taking Rosuvastatin OpeN label [CHARON; NCT01078675] and Study 4522IL/0086) were used to describe rosuvastatin pharmacokinetics in patients with heterozygous familial hypercholesterolemia aged ≥6 to <18 years. Methods Rosuvastatin concentration-time data were analyzed via non-linear mixed-effects modeling (NONMEM), with clearance (CL/F) as the pre-defined key pharmacokinetic parameter of interest. In addition, descriptive comparisons between pediatric patients and adults (healthy and dyslipidemic) were performed. The dataset included 214 pediatric patients, with 2,029 rosuvastatin concentrations. Results A linear two-compartment model with first-order absorption and elimination processes adequately described the combined dataset. Weight and gender were significant covariates for CL/F, with moderate between-patient variability remaining (coefficient of variation (CV) 40 %): CL/F in female children was approximately 30 % lower than in male children, and there was a twofold mean difference in CL/F across the observed weight range. Age was not a significant covariate after accounting for weight and gender differences. However, weight and gender only reduced between-patient variability from 45 (without covariates) to 40 % and are considered unlikely to be clinically relevant. Conclusions Rosuvastatin pharmacokinetics appeared generally predictable with respect to dose, and time (study duration) and the exposure (dose-normalized area under the plasma concentration-time curve at steady state (AUC ss)) in children and adolescents appeared to be similar or lower than adult patients with dyslipidemia.

Research paper thumbnail of Population pharmacokinetics of esomeprazole in adult patients with gastroesophageal reflux disease

Clinical Pharmacology & Therapeutics, Feb 1, 2005

ABSTRACT

Research paper thumbnail of Safety and Tolerability of Physcion in Healthy Volunteers in a Phase I Dose Escalating Clinical Pharmacology Study

Gastroenterology, May 1, 2011

Research paper thumbnail of Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery

European Journal of Clinical Pharmacology, 1997

Objective Pharmacokinetics and haemodynamic effects of a total dose of 15 µg·kg-1 sufentanil, an... more Objective Pharmacokinetics and haemodynamic effects of a total dose of 15 µg·kg-1 sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) µg·kg-1·min-1, respectively. Results Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there

Research paper thumbnail of Pharmacokinetic/pharmacodynamic relationship of the duration of vasodilating action of organic mononitrates in rats

PubMed, May 1, 1992

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the du... more Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (T1/2). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the classical Hill equation, with similar slope but different EC50 values. A duration of action, defined as the time taken for the pulse pressure to change from -30% to -20% from base line, was measured experimentally. Theoretical analysis suggests that a linear relationship should exist between this duration of action and T1/2/slope, and this was indeed observed (r = 0.99, P less than .01, n = 12), affirming the dependency of pulse pressure pharmacodynamics on the pharmacokinetics of organic mononitrates. Pharmacokinetic modeling of the in vivo time-dependent hemodynamic effects further indicated that the blood compartment data were more consistent with a mechanism of mononitrate action that involves metabolic activation to form nitric oxide and cyclic GMP, rather than direct receptor activation. Using this pharmacodynamic model, the in vivo half-lives of nitric oxide and cGMP were estimated to be 1.6 and 2.0 min, respectively.

Research paper thumbnail of Sensitive capillary gas chromatographic-mass spectrometric-selected-ion monitoring method for the determination of diclofenac concentrations in human plasma

Journal of Chromatography B: Biomedical Sciences and Applications, 1996

We have modified and validated a capillary GC-MS method reported by Kadowaki et al. [J. Chromatog... more We have modified and validated a capillary GC-MS method reported by Kadowaki et al. [J. Chromatogr., 308 (1984) 329] fi)r the determination of diclofenac in human plasma by using heptane rather than benzene as an extraction agent. In addition, acetone was added to the samples as a deproteination agent which increased the recovery of diclofenac. These revised processes allowed clean extraction and near-quantitative recovery of analyte (>95%). Separation was achieved on an HP-1 column with helium as carrier gas. The parent ion peaks of diclofenac (m/z 277) and the internal standard, 4'-methoxydiclofenac (m/z 307), were monitored by a mass-selective detector using the selected-ion monitoring mode. The linear range for the routine assay was from 5 to 2000 ng/ml, The detection and lower quantifiable limits were 0.2 and I ng/ml, respectively, with no interference from plasma. The within-day and between-day coefficients of variation for high and medium concentrations were less than 5% and were less than 13% fl)r lo~ concentrations (10 ng/ml). This GC-MS assay method has been used t\~r pharmacokinetic and drug interaction studies in humans.

Research paper thumbnail of Development and validation of a sensitive analytical method for the simultaneous determination of buprenorphine and norbuprenorphine in human plasma

European Journal of Pharmaceutics and Biopharmaceutics, 2001

A sensitive, speci®c, and robust capillary gas chromatography±mass spectrometry method has been d... more A sensitive, speci®c, and robust capillary gas chromatography±mass spectrometry method has been developed and validated for simultaneous determination of buprenorphine and its active metabolite, norbuprenorphine, in human plasma. Sample preparation involved a cleanup procedure using a Bond Elut Certify cartridge followed by derivatization with penta¯uoropropionic anhydride. Separation was carried out on a HP-1 fused silica capillary column using helium as the carrier gas. Selected ion monitoring was used in the electron impact mode. Excellent linearity was found between 0.10 and 20.0 ng/ml with a limit of quantitation of 0.05 and 0.10 ng/ml for buprenorphine and norbuprenorphine, respectively. Interday and intraday assay precisions (%CV) and accuracies were within 15.0% for buprenorphine and norbuprenorphine, respectively. Recoveries were quantitative and concentration-independent. This method will be applied to pharmacokinetic/pharmacodynamic/bioequivalence studies of buprenorphine in humans.

Research paper thumbnail of Pharmacokinetic Interactions between Zileuton and Prednisone

Clinical Pharmacokinetics, 1995

A randomized double-blind placebo-controlled crossover study evaluated the effects of zileuton 60... more A randomized double-blind placebo-controlled crossover study evaluated the effects of zileuton 600mg 4 time daily on the pharmacokinetics of prednisolone after a single 400mg oral dose of prednisone. the effects of the single prednisone dose on the steady-state pharmacokinetics of zileuton were also evaluated. Multiple doses of zileuton had no significant effects on mean peak plasma concentration (Cmax), time to Cmax(tmax), or area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity) values for prednisolone after oral administration of prednisone 40mg. A slight but statistically significant increase in the mean half-life (t1/2) of prednisolone was detected with zileuton + prednisone administration compared with prednisone + placebo (from 2.8 to 2.9 hours); however, this change was of no clinical relevance. Mean Cmax values of zileuton after coadministration with prednisone were similar to those of zileuton alone. While the single 40mg dose of prednisone resulted in a slight but statistically significant decrease in the mean zileuton AUC value from 0 to 6 hours (AUC0-6) [from 23 to 20 mg/L/h] and a reduction in tMAX (from 2.3 to 1.7 hours), these results were not considered to be clinically significant. Therefore, it is considered that zileuton and prednisone may be coadministered with minimal risk of a clinically significant pharmacokinetic interaction.

Research paper thumbnail of Pharmacokinetics of oral L-isoidide mononitrate in rats

Biopharmaceutics & Drug Disposition, 1993

L-isoidide mononitrate (L-IIMN) is the most potent mononitrate vasodilator described so far in th... more L-isoidide mononitrate (L-IIMN) is the most potent mononitrate vasodilator described so far in the literature. Since other mononitrates, such as isosorbide-5-mononitrate and isosorbide-2-mononitrate, have been shown not to be subject to first-pass metabolism, we examined the pharmacokinetics of L-IIMN after oral administration to determine whether this compound also exhibited this behavior. An oral dose of 2 mg kg-1 L-IIMN dissolved in normal saline was given to seven rats. Absorption of L-IIMN after dosing was rapid with an apparent absorption half-life of 9.5 +/- 3.6 min (mean +/- SD). Plasma L-IIMN concentrations peaked between 5 and 20 min after dosing and declined thereafter in an apparently monoexponential manner. The average elimination half-life was 11.9 +/- 1.7 min (mean +/- SD). Oral bioavailability was estimated to be about 50%. Thus, unlike the other mononitrates so far examined in the literature, L-IIMN exhibits incomplete bioavailability. This pharmacokinetic behavior, however, is consistent with its faster systemic clearance compared to other organic mononitrates.

Research paper thumbnail of Characterization of the pharmacokinetics of buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine

European Journal of Pharmaceutical Sciences, 2002

Research paper thumbnail of Pharmacokinetic/Pharmacodynamic Correlations of Selected Vasodilators

Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019

Research paper thumbnail of Pharmacokinetics of stereomeric 1,4:3,6-dianhydrohexitol mononitrates in rats

Pharmaceutical research, 1993

The pharmacokinetics and urinary recoveries of four isomeric mononitrates, L-isoidide mononitrate... more The pharmacokinetics and urinary recoveries of four isomeric mononitrates, L-isoidide mononitrate (L-IIMN), isosorbide-2-mononitrate (IS-2-MN), isomannide mononitrate (IMMN), and isosorbide-5-mononitrate (IS-5-MN), were investigated at an intravenous dose of 2 mg/kg in rats. All four compounds exhibited monoexponential kinetics at this dose. The volumes of distribution were similar for all four isomers and were estimated at about 1.0 liter/kg. The systemic clearances of L-IIMN, IMMN, IS-2-MN, and IS-5-MN were 65.1 +/- 13.0, 32.7 +/- 12.0, 11.0 +/- 2.3, and 8.23 +/- 1.82 ml/min/kg, respectively (P < 0.05, all pairwise comparisons). Free mononitrate in the urine accounted for 0.306 to 4.56% of the administered dose, while the recovery in conjugated forms (after glusulase hydrolysis) accounted for 42.8% of the IMMN dose and 7.70 to 14.5% of the dose of the remaining three isomers. The dose-dependent pharmacokinetics of three of the mononitrates were explored at selected higher doses...

Research paper thumbnail of Apparent thermodynamic parameters of ligand binding to the cloned rat μ-opioid receptor

European Journal of Pharmacology, 1998

The apparent thermodynamic parameters of binding of ten ligands to the cloned rat mu-opioid recep... more The apparent thermodynamic parameters of binding of ten ligands to the cloned rat mu-opioid receptor stably expressed in Chinese hamster ovary (CHO) cells were investigated. For every ligand, the Kd or Ki values at 0 degrees C, 12 degrees C, 25 degrees C and 37 degrees C were determined, a van&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;t Hoff plot was generated and deltaH degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; , deltaS degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and -TdeltaS degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and deltaG degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; were calculated. Changes in free energy (deltaG degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;) ranged from -10.35 to -15.65 kcal/mol. The binding of sufentanil, ohmefentanyl, diprenorphine and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-penicillamineThr-NH2 (CTAP) was endothermic (deltaH degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0) and driven by an increase in entropy (-TdeltaS degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; = -13.08 to -18.57 kcal/mol). The binding of naltrexone was exothermic (deltaH degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; = -12.56 kcal/mol) and essentially enthalpy-driven. The binding of morphine, methadone, pentazocine, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) was exothermic (deltaH degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; = -3.53 to -9.95 kcal/mol) and occurred with an increase in entropy (-TdeltaS degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; = -2.48 to -7.92 kcal/mol). Plots of enthalpy versus entropy and enthalpy versus free energy were linear, although enthalpy-entropy compensation was not evident. The entropy changes were not correlated with apparent lipophilicity of the compounds. These results suggest that: (1) opioid ligands bind to the mu receptor by specific mechanisms, unrelated to lipid solubility; (2) the mechanism of binding is not universally different for peptide and non-peptide ligands; (3) the nature of binding does not a priori determine intrinsic activity. The results reveal a novel differentiation of opioid ligands into two groups (group 1: ohmefentanyl, sufentanil, diprenorphine, CTAP and PL017; group 2: naltrexone, morphine, methadone, DAMGO, pentazocine), based on two distinct relationships between enthalpy versus free energy of binding, the details of which are yet to be elucidated.

Research paper thumbnail of Structure activity relationship of organic nitrates: an exploratory hypothesis via molecular models

Medical Hypotheses, 1992

An exploratory attempt to explain the structure/activity relationship of organic nitrates was ini... more An exploratory attempt to explain the structure/activity relationship of organic nitrates was initiated. In addition to the partition coefficient, a new empirical parameter, F(58A), was used in this correlation. This new parameter denotes the number of times that two oxygen atoms in the molecule can be arranged at a distance of 5.8A. Vasodilating potencies (ECaes) and partition coefficients of 11 organic nitrates were obtained from a literature report, while their corresponding F(58A) values were obtained from manual determination using two molecular models, viz: CPK and Drieding. Via linear regression comparisons, we showed that F(58A) was a better physicochemical parameter than the partition coefficient in explaining the differences in the observed pharmacologic activity. When the two parameters were combined, >90% of the variability of the potency was accounted for. These results suggest that the pertinent protein (most likely the activating enzyme) for organic nitrate activity may contain at least two 'oxygen-philic' attachment sites which are separated by a distance of 5.8A.

Research paper thumbnail of Pharmacodynamic modeling of thein vitro vasodilating effects of organic mononitrates

The in vitro dose-relaxation curves of four isomeric organic mononitrates: L-isoidide mononitrate... more The in vitro dose-relaxation curves of four isomeric organic mononitrates: L-isoidide mononitrate (L-IIMN), isosorbide-2-mononitrate (IS-2-MN), isomannide mononitrate (IMMN), and isosorbide-5-mononitrate (IS-5-MN), were determined with rat aorta rings. These mononitrates relaxed vascular tissue in a concentration-dependent manner.

Research paper thumbnail of Gas chromatographic analysis of isomeric organic mononitrates in plasma

Journal of chromatography, Jan 15, 1991

A specific, sensitive and precise capillary gas chromatographic method using electron-capture det... more A specific, sensitive and precise capillary gas chromatographic method using electron-capture detection was developed for the determination of four isomeric vasodilating organic mononitrates, viz. L-isoidide mononitrate (L-IIMN), isosorbide-2-mononitrate (IS-2-MN), isomannide mononitrate (IMMN) and isosorbide-5-mononitrate (IS-5-MN), in rat plasma. With a sample size of 100 microliters of rat plasma, the detection limits were found to be between 0.5 and 2 ng/ml for these mononitrates, and the absolute recovery was found to range from 83 to 90%. The within-day coefficients of variation for the assay of the four isomers were less than 5%, while the between-day coefficients of variation were less than 10%. Because of the short retention times of these isomers in this assay, routine analyses of about sixty plasma samples per day can be carried out. The possibility of in vivo interconversion among these four isomers in rats was investigated after individual administration of each isomer....

Research paper thumbnail of Pharmacokinetic/Pharmacodynamic Relationship of the Duration of Vasodilating Action of Organic Mononitrates in Rats1

J Pharmacol and Exp Ther, 1992

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the du... more Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (Tn). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the dassical Hill equation, with similar slope but different EC

Research paper thumbnail of Pharmacokinetic/Pharmacodynamic Relationship of the Duration of Vasodilating Action of Organic Mononitrates in Rats1

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the du... more Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (Tn). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the dassical Hill equation, with similar slope but different EC

Research paper thumbnail of Pharmacokinetic/Pharmacodynamic Relationship of the Duration of Vasodilating Action of Organic Mononitrates in Rats1

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the du... more Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (Tn). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the dassical Hill equation, with similar slope but different EC

Research paper thumbnail of Absorption Kinetics of Diclofenac in Dental Patients After Molar Extraction

Clinical Pharmacology & Therapeutics, Feb 1, 1996

ABSTRACT

Research paper thumbnail of Population pharmacokinetics of rosuvastatin in normal subjects and subjects with dyslipidemia

Clinical Pharmacology & Therapeutics, Feb 1, 2004

Purpose Data from two clinical studies (hyperCholesterolaemia in cHildren and Adolescents taking ... more Purpose Data from two clinical studies (hyperCholesterolaemia in cHildren and Adolescents taking Rosuvastatin OpeN label [CHARON; NCT01078675] and Study 4522IL/0086) were used to describe rosuvastatin pharmacokinetics in patients with heterozygous familial hypercholesterolemia aged ≥6 to <18 years. Methods Rosuvastatin concentration-time data were analyzed via non-linear mixed-effects modeling (NONMEM), with clearance (CL/F) as the pre-defined key pharmacokinetic parameter of interest. In addition, descriptive comparisons between pediatric patients and adults (healthy and dyslipidemic) were performed. The dataset included 214 pediatric patients, with 2,029 rosuvastatin concentrations. Results A linear two-compartment model with first-order absorption and elimination processes adequately described the combined dataset. Weight and gender were significant covariates for CL/F, with moderate between-patient variability remaining (coefficient of variation (CV) 40 %): CL/F in female children was approximately 30 % lower than in male children, and there was a twofold mean difference in CL/F across the observed weight range. Age was not a significant covariate after accounting for weight and gender differences. However, weight and gender only reduced between-patient variability from 45 (without covariates) to 40 % and are considered unlikely to be clinically relevant. Conclusions Rosuvastatin pharmacokinetics appeared generally predictable with respect to dose, and time (study duration) and the exposure (dose-normalized area under the plasma concentration-time curve at steady state (AUC ss)) in children and adolescents appeared to be similar or lower than adult patients with dyslipidemia.

Research paper thumbnail of Population pharmacokinetics of esomeprazole in adult patients with gastroesophageal reflux disease

Clinical Pharmacology & Therapeutics, Feb 1, 2005

ABSTRACT

Research paper thumbnail of Safety and Tolerability of Physcion in Healthy Volunteers in a Phase I Dose Escalating Clinical Pharmacology Study

Gastroenterology, May 1, 2011

Research paper thumbnail of Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery

European Journal of Clinical Pharmacology, 1997

Objective Pharmacokinetics and haemodynamic effects of a total dose of 15 µg·kg-1 sufentanil, an... more Objective Pharmacokinetics and haemodynamic effects of a total dose of 15 µg·kg-1 sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) µg·kg-1·min-1, respectively. Results Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there

Research paper thumbnail of Pharmacokinetic/pharmacodynamic relationship of the duration of vasodilating action of organic mononitrates in rats

PubMed, May 1, 1992

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the du... more Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (T1/2). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the classical Hill equation, with similar slope but different EC50 values. A duration of action, defined as the time taken for the pulse pressure to change from -30% to -20% from base line, was measured experimentally. Theoretical analysis suggests that a linear relationship should exist between this duration of action and T1/2/slope, and this was indeed observed (r = 0.99, P less than .01, n = 12), affirming the dependency of pulse pressure pharmacodynamics on the pharmacokinetics of organic mononitrates. Pharmacokinetic modeling of the in vivo time-dependent hemodynamic effects further indicated that the blood compartment data were more consistent with a mechanism of mononitrate action that involves metabolic activation to form nitric oxide and cyclic GMP, rather than direct receptor activation. Using this pharmacodynamic model, the in vivo half-lives of nitric oxide and cGMP were estimated to be 1.6 and 2.0 min, respectively.

Research paper thumbnail of Sensitive capillary gas chromatographic-mass spectrometric-selected-ion monitoring method for the determination of diclofenac concentrations in human plasma

Journal of Chromatography B: Biomedical Sciences and Applications, 1996

We have modified and validated a capillary GC-MS method reported by Kadowaki et al. [J. Chromatog... more We have modified and validated a capillary GC-MS method reported by Kadowaki et al. [J. Chromatogr., 308 (1984) 329] fi)r the determination of diclofenac in human plasma by using heptane rather than benzene as an extraction agent. In addition, acetone was added to the samples as a deproteination agent which increased the recovery of diclofenac. These revised processes allowed clean extraction and near-quantitative recovery of analyte (>95%). Separation was achieved on an HP-1 column with helium as carrier gas. The parent ion peaks of diclofenac (m/z 277) and the internal standard, 4'-methoxydiclofenac (m/z 307), were monitored by a mass-selective detector using the selected-ion monitoring mode. The linear range for the routine assay was from 5 to 2000 ng/ml, The detection and lower quantifiable limits were 0.2 and I ng/ml, respectively, with no interference from plasma. The within-day and between-day coefficients of variation for high and medium concentrations were less than 5% and were less than 13% fl)r lo~ concentrations (10 ng/ml). This GC-MS assay method has been used t\~r pharmacokinetic and drug interaction studies in humans.

Research paper thumbnail of Development and validation of a sensitive analytical method for the simultaneous determination of buprenorphine and norbuprenorphine in human plasma

European Journal of Pharmaceutics and Biopharmaceutics, 2001

A sensitive, speci®c, and robust capillary gas chromatography±mass spectrometry method has been d... more A sensitive, speci®c, and robust capillary gas chromatography±mass spectrometry method has been developed and validated for simultaneous determination of buprenorphine and its active metabolite, norbuprenorphine, in human plasma. Sample preparation involved a cleanup procedure using a Bond Elut Certify cartridge followed by derivatization with penta¯uoropropionic anhydride. Separation was carried out on a HP-1 fused silica capillary column using helium as the carrier gas. Selected ion monitoring was used in the electron impact mode. Excellent linearity was found between 0.10 and 20.0 ng/ml with a limit of quantitation of 0.05 and 0.10 ng/ml for buprenorphine and norbuprenorphine, respectively. Interday and intraday assay precisions (%CV) and accuracies were within 15.0% for buprenorphine and norbuprenorphine, respectively. Recoveries were quantitative and concentration-independent. This method will be applied to pharmacokinetic/pharmacodynamic/bioequivalence studies of buprenorphine in humans.

Research paper thumbnail of Pharmacokinetic Interactions between Zileuton and Prednisone

Clinical Pharmacokinetics, 1995

A randomized double-blind placebo-controlled crossover study evaluated the effects of zileuton 60... more A randomized double-blind placebo-controlled crossover study evaluated the effects of zileuton 600mg 4 time daily on the pharmacokinetics of prednisolone after a single 400mg oral dose of prednisone. the effects of the single prednisone dose on the steady-state pharmacokinetics of zileuton were also evaluated. Multiple doses of zileuton had no significant effects on mean peak plasma concentration (Cmax), time to Cmax(tmax), or area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity) values for prednisolone after oral administration of prednisone 40mg. A slight but statistically significant increase in the mean half-life (t1/2) of prednisolone was detected with zileuton + prednisone administration compared with prednisone + placebo (from 2.8 to 2.9 hours); however, this change was of no clinical relevance. Mean Cmax values of zileuton after coadministration with prednisone were similar to those of zileuton alone. While the single 40mg dose of prednisone resulted in a slight but statistically significant decrease in the mean zileuton AUC value from 0 to 6 hours (AUC0-6) [from 23 to 20 mg/L/h] and a reduction in tMAX (from 2.3 to 1.7 hours), these results were not considered to be clinically significant. Therefore, it is considered that zileuton and prednisone may be coadministered with minimal risk of a clinically significant pharmacokinetic interaction.

Research paper thumbnail of Pharmacokinetics of oral L-isoidide mononitrate in rats

Biopharmaceutics & Drug Disposition, 1993

L-isoidide mononitrate (L-IIMN) is the most potent mononitrate vasodilator described so far in th... more L-isoidide mononitrate (L-IIMN) is the most potent mononitrate vasodilator described so far in the literature. Since other mononitrates, such as isosorbide-5-mononitrate and isosorbide-2-mononitrate, have been shown not to be subject to first-pass metabolism, we examined the pharmacokinetics of L-IIMN after oral administration to determine whether this compound also exhibited this behavior. An oral dose of 2 mg kg-1 L-IIMN dissolved in normal saline was given to seven rats. Absorption of L-IIMN after dosing was rapid with an apparent absorption half-life of 9.5 +/- 3.6 min (mean +/- SD). Plasma L-IIMN concentrations peaked between 5 and 20 min after dosing and declined thereafter in an apparently monoexponential manner. The average elimination half-life was 11.9 +/- 1.7 min (mean +/- SD). Oral bioavailability was estimated to be about 50%. Thus, unlike the other mononitrates so far examined in the literature, L-IIMN exhibits incomplete bioavailability. This pharmacokinetic behavior, however, is consistent with its faster systemic clearance compared to other organic mononitrates.

Research paper thumbnail of Characterization of the pharmacokinetics of buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine

European Journal of Pharmaceutical Sciences, 2002

Research paper thumbnail of Pharmacokinetic/Pharmacodynamic Correlations of Selected Vasodilators

Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019

Research paper thumbnail of Pharmacokinetics of stereomeric 1,4:3,6-dianhydrohexitol mononitrates in rats

Pharmaceutical research, 1993

The pharmacokinetics and urinary recoveries of four isomeric mononitrates, L-isoidide mononitrate... more The pharmacokinetics and urinary recoveries of four isomeric mononitrates, L-isoidide mononitrate (L-IIMN), isosorbide-2-mononitrate (IS-2-MN), isomannide mononitrate (IMMN), and isosorbide-5-mononitrate (IS-5-MN), were investigated at an intravenous dose of 2 mg/kg in rats. All four compounds exhibited monoexponential kinetics at this dose. The volumes of distribution were similar for all four isomers and were estimated at about 1.0 liter/kg. The systemic clearances of L-IIMN, IMMN, IS-2-MN, and IS-5-MN were 65.1 +/- 13.0, 32.7 +/- 12.0, 11.0 +/- 2.3, and 8.23 +/- 1.82 ml/min/kg, respectively (P < 0.05, all pairwise comparisons). Free mononitrate in the urine accounted for 0.306 to 4.56% of the administered dose, while the recovery in conjugated forms (after glusulase hydrolysis) accounted for 42.8% of the IMMN dose and 7.70 to 14.5% of the dose of the remaining three isomers. The dose-dependent pharmacokinetics of three of the mononitrates were explored at selected higher doses...

Research paper thumbnail of Apparent thermodynamic parameters of ligand binding to the cloned rat μ-opioid receptor

European Journal of Pharmacology, 1998

The apparent thermodynamic parameters of binding of ten ligands to the cloned rat mu-opioid recep... more The apparent thermodynamic parameters of binding of ten ligands to the cloned rat mu-opioid receptor stably expressed in Chinese hamster ovary (CHO) cells were investigated. For every ligand, the Kd or Ki values at 0 degrees C, 12 degrees C, 25 degrees C and 37 degrees C were determined, a van&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;t Hoff plot was generated and deltaH degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; , deltaS degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and -TdeltaS degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and deltaG degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; were calculated. Changes in free energy (deltaG degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;) ranged from -10.35 to -15.65 kcal/mol. The binding of sufentanil, ohmefentanyl, diprenorphine and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-penicillamineThr-NH2 (CTAP) was endothermic (deltaH degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0) and driven by an increase in entropy (-TdeltaS degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; = -13.08 to -18.57 kcal/mol). The binding of naltrexone was exothermic (deltaH degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; = -12.56 kcal/mol) and essentially enthalpy-driven. The binding of morphine, methadone, pentazocine, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) was exothermic (deltaH degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; = -3.53 to -9.95 kcal/mol) and occurred with an increase in entropy (-TdeltaS degrees&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; = -2.48 to -7.92 kcal/mol). Plots of enthalpy versus entropy and enthalpy versus free energy were linear, although enthalpy-entropy compensation was not evident. The entropy changes were not correlated with apparent lipophilicity of the compounds. These results suggest that: (1) opioid ligands bind to the mu receptor by specific mechanisms, unrelated to lipid solubility; (2) the mechanism of binding is not universally different for peptide and non-peptide ligands; (3) the nature of binding does not a priori determine intrinsic activity. The results reveal a novel differentiation of opioid ligands into two groups (group 1: ohmefentanyl, sufentanil, diprenorphine, CTAP and PL017; group 2: naltrexone, morphine, methadone, DAMGO, pentazocine), based on two distinct relationships between enthalpy versus free energy of binding, the details of which are yet to be elucidated.

Research paper thumbnail of Structure activity relationship of organic nitrates: an exploratory hypothesis via molecular models

Medical Hypotheses, 1992

An exploratory attempt to explain the structure/activity relationship of organic nitrates was ini... more An exploratory attempt to explain the structure/activity relationship of organic nitrates was initiated. In addition to the partition coefficient, a new empirical parameter, F(58A), was used in this correlation. This new parameter denotes the number of times that two oxygen atoms in the molecule can be arranged at a distance of 5.8A. Vasodilating potencies (ECaes) and partition coefficients of 11 organic nitrates were obtained from a literature report, while their corresponding F(58A) values were obtained from manual determination using two molecular models, viz: CPK and Drieding. Via linear regression comparisons, we showed that F(58A) was a better physicochemical parameter than the partition coefficient in explaining the differences in the observed pharmacologic activity. When the two parameters were combined, >90% of the variability of the potency was accounted for. These results suggest that the pertinent protein (most likely the activating enzyme) for organic nitrate activity may contain at least two 'oxygen-philic' attachment sites which are separated by a distance of 5.8A.

Research paper thumbnail of Pharmacodynamic modeling of thein vitro vasodilating effects of organic mononitrates

The in vitro dose-relaxation curves of four isomeric organic mononitrates: L-isoidide mononitrate... more The in vitro dose-relaxation curves of four isomeric organic mononitrates: L-isoidide mononitrate (L-IIMN), isosorbide-2-mononitrate (IS-2-MN), isomannide mononitrate (IMMN), and isosorbide-5-mononitrate (IS-5-MN), were determined with rat aorta rings. These mononitrates relaxed vascular tissue in a concentration-dependent manner.

Research paper thumbnail of Gas chromatographic analysis of isomeric organic mononitrates in plasma

Journal of chromatography, Jan 15, 1991

A specific, sensitive and precise capillary gas chromatographic method using electron-capture det... more A specific, sensitive and precise capillary gas chromatographic method using electron-capture detection was developed for the determination of four isomeric vasodilating organic mononitrates, viz. L-isoidide mononitrate (L-IIMN), isosorbide-2-mononitrate (IS-2-MN), isomannide mononitrate (IMMN) and isosorbide-5-mononitrate (IS-5-MN), in rat plasma. With a sample size of 100 microliters of rat plasma, the detection limits were found to be between 0.5 and 2 ng/ml for these mononitrates, and the absolute recovery was found to range from 83 to 90%. The within-day coefficients of variation for the assay of the four isomers were less than 5%, while the between-day coefficients of variation were less than 10%. Because of the short retention times of these isomers in this assay, routine analyses of about sixty plasma samples per day can be carried out. The possibility of in vivo interconversion among these four isomers in rats was investigated after individual administration of each isomer....